Oxygen is one of the basic essentials for sustaining life. Today's medical technology can supply oxygen to patients experiencing pulmonary failure, otherwise known as respiratory failure. Pulmonary failure occurs when the lungs experience significant damage and are unable to supply the body and brain with oxygen. Pulmonary failure may be caused by a variety of conditions including, for example, lung cancer, physical trauma, acute respiratory distress syndrome (ARDS), aerosolized bioterrorism agents, and diseases such as severe acute respiratory syndrome (SARS), pneumonia, tuberculosis, sepsis, and other bacterial or viral infections, physical trauma, and chemical or smoke inhalation. Currently, oxygen can be supplied to patients experiencing pulmonary failure through mechanical ventilation (MV) or extracorporeal membrane oxygenation (ECMO). However, the mortality rate of patients receiving oxygen through MV or ECMO remains high.
MV has been an ineffective method for delivering oxygen to the body in certain cases because oxygen exchange is decreased by damage to the lung and because of increased stress caused to the injured lung by the treatment. As an example, for patients experiencing severe hypoxemia arising from lung injury MV may be inadequate owing to limited mass transfer in the injured lung; over-inflation, barotrauma and cyclic closing and reopening of the alveoli may further damage the lung and trigger a pulmonary and systemic inflammatory reaction that may lead to multiple system organ failure.
ECMO is a temporary artificial extracorporeal support of the respiratory system and/or cardiac system. ECMO was first used in an adult in 1972 to treat severe respiratory failure and in 1974 on the first newborn. Innovations in ECMO include the introduction of polymethylpentene hollow fibers with non thrombogenic coatings and thin wire-reinforced cannula walls. ECMO use has historically centered on neonatal care. However, ECMO is an expensive alternative therapy with limited availability in hospitals and length of treatment. ECMO is able to bypass the injured lungs to deliver oxygen and allow the lungs to heal, however there is a high risk of thrombosis and contamination of the blood because it is removed from the body. Since ECMO is associated with significant complications, sometimes additional therapies are required such as the use of anticoagulants (heparin is standard). However, anticoagulants are often administered to the patient leading to additional adverse side effects. Additionally, ECMO is expensive and complex to operate, limiting its accessibility for emergency care.
Because of the high mortality rate, methods of bypassing the lungs and delivering oxygen directly to the body have been explored for many years. Research has focused on peritoneal oxygenation as a method of extrapulmonary respiration. The exchange of oxygen and carbon dioxide occurs through the large surface area of the membrane that lines the abdominal cavity, the peritoneum.
Previous methods include in situ extrapulmonary ventilation (EV). Success in oxygenating blood in situ has been achieved by circulating fluorocarbons, blood, and liposome-encapsulated hemoglobin (a synthetic oxygen carrier) through the intraperitoneal (IP) space, or cavity. Additional previous methods include the study of carriers for the delivery of oxygen. Carriers have included blood, perfluorocarbon (PFC), and synthetic hemoglobin carriers, for example TRM-645, which are effective. In contrast, pure oxygen gas has been shown not to be an effective carrier. None of the effective carriers, however, are both safe and economical. For example, PFCs are expensive to generate and evaporate into potent greenhouse gases creating a significant environmental concern. They are also very stable, tending to accumulate in biological systems in which they are used. Blood and products derived from blood (like synthetic hemoglobin carriers) suffer from scarcity and are relatively expensive to fabricate and store. Furthermore, EV ventilation requires high volumes of perfusate; therefore, a fluid that is economical and biodegradable is important. In additional, none of the previously developed methods have achieved certain components for extrapulmonary respiration: (1) delivery of an adequate supply of oxygen, (2) long-term safety for the patient, and (3) cost-effectiveness.
Another form of therapy explored to deliver oxygen systematically by circulating it through the IP space is a method that uses an oxygen microbubble (OMB) carrier. OMBs are oxygen filled bubbles that have a shell composed of a phospholipid monolayer. The phospholipid monolayer shell of an OMB has similar composition to lung surfactant and requires comparable physical properties, such as rapid adsorption to and mechanical stabilization of the gas/liquid interface and high gas permeability. Thus OMBs are also designed to mimic the mechanical and gas transport properties of the alveolus to deliver the oxygen payload and uptake carbon dioxide.
Previous research has focused on the delivery of OMBs through intravenous (IV) oxygen delivery. However, IV injection of OMBs is a one-way administration and does not allow for the circulation of microbubbles into and out of the body to both deliver oxygen and remove carbon dioxide. Delivering oxygen using and IV appears to be a promising method for short-term rescue, but the prolonged continuous infusion of oxygen microbubbles into the bloodstream poses significant challenges for clinical translation, including the potential for embolism, thrombosis, immunogenicity and toxicities of lipid and saline load. For example, with IV injection of OMBs, any oxygen inspired through the lungs can be absorbed by the microbubbles and can cause long-circulating bubbles that may cause embolism or other problematic conditions, such as those observed in decompression sickness. Further, with the potential for embolism, IV injection of microbubbles requires a strict upper limit on the microbubble size (<10 micrometers) and on the microbubble volume fraction (<70%).
Still another problem with IV injection of OMBs is that any nitrogen inspired through the lungs, such as that found in air, will be absorbed by the microbubbles. Thus, the microbubbles will exchange oxygen for nitrogen. The nitrogen-containing microbubbles will be persistent, which can lead to serious problems, such as those observed during decompression sickness and embolism (thus leading to severe morbidity and death). In addition, intravenous oxygenation using OMBs cannot support long-term ventilation due to the lipid and saline load from continuous infusion.
A demand therefore exists for a system and method for delivery of oxygen to a subject that is more effective and efficient than the current systems and methods presently available. The invention satisfies this demand.